Human plasmacytoid dendritic cells interact with gp96 via CD91 and regulate inflammatory responses.
Glucose-regulated stress protein gp96 is known to be involved in the host response to pathogens and to cancer. Our study explored the relationships between gp96 and human blood plasmacytoid dendritic cells (pDC) and proved that gp96 directly targets pDC by a receptor-dependent interaction. Competition studies identified CD91 as a gp96 receptor on pDC, and laser confocal imaging indicated that CD91 triggering was followed by gp96 endocytosis and trafficking into early endosomes and later into the endoplasmic reticulum compartment. Using two alternative Abs, we showed that human blood pDC reproducibly expressed CD91, although different levels of expression were detectable among the analyzed donors. Moreover, CpG-matured pDC displayed CD91 receptor up-regulation that correlated with an increased gp96 binding. Functionally, gp96-pDC interaction activated the NF-kappaB pathway, leading to the nuclear translocation of the NF-kappaB complex. gp96-treated pDC maintained an immature phenotype, while they down-modulated the release of IL-8, suggesting an anti-inflammatory role of this pathway, and they strongly up-regulated the cell surface expression of the gp96 receptor CD91. CpG-matured or gp96-treated pDC, expressing high levels of the gp96 receptor CD91, antagonized the gp96-induced activation of monocyte-derived dendritic cells in terms of cell surface phenotype and cytokine production. Altogether, these results suggest that gp96-pDC interaction might represent an active mechanism controlling the strength of the immune response to free, extracellular available gp96; this mechanism could be particularly relevant in wounds and chronic inflammation.
De Filippo
AnnaMaria
A
Unit of Immunotherapy of Human Tumours, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milano, Italy.
Binder
Robert J
RJ
Camisaschi
Chiara
C
Beretta
Valeria
V
Arienti
Flavio
F
Villa
Antonello
A
Della Mina
Pamela
P
Parmiani
Giorgio
G
Rivoltini
Licia
L
Castelli
Chiara
C
D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology
D015703:Antigens, CD; D018836:Inflammation Mediators; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; C053387:endoplasmin